98 results about "Co-stimulation" patented technology

The present invention is directed to a monoclonal anti-human CS1 clone 7A8D5 antibody or a single-chain variable fragment (scFv), comprising VH having the amino acid of SEQ ID NO: 4 and VL having the amino acid of SEQ ID NO: 5. The present invention is also directed to a chimeric antigen receptor fusion protein comprising from N-terminus to C-terminus: (i) CS1 scFv of the present invention, (ii) a transmembrane domain, (iii) at least one co-stimulatory domains, and (iv) an activating domain.

The invention relates to a chimeric T-cell receptor (TCR) comprising a human transmembrane domain, a human intracellular domain and a human intracellular CD3ε domain wherein in at least one of the CD3ε domains, an arginine (R) amino acid residue at position 53 and / or 54 of SEQ ID NO:25, or an arginine (R) amino acid residue at a position that corresponds to said arginine (R) amino acid residue at position 54 of SEQ ID NO:25, is substituted or deleted. The invention further relates to a method of producing a T-cell expressing the chimeric co-stimulatory TCR. The invention further relates to a chimeric T-cell receptor (TCR) comprising a human co-stimulatory domain and a human CD3ε domain. The invention further relates to a method of treating a patient having a tumor or an immune-related disease comprising administering T-cells expressing the chimeric TCR to the patient.

The present invention is directed to a humanized BCMA single-chain variable fragment (scFv), comprising VH having the amino acid sequence of SEQ ID NO: 4 and VL having the amino acid sequence of SEQ ID NO: 5. The present invention is also directed to a BCMA chimeric antigen receptor fusion protein comprising from N-terminus to C-terminus: (i) a single-chain variable fragment (scFv) of the present invention, (ii) a transmembrane domain, (iii) at least one co-stimulatory domains, and (iv) an activating domain. This humanized BCMA-CAR-T cells have specific killing activity with secretion of cytokine IFN-gamma in CAR-T cells in vitro and in vivo.

The present invention relates to multispecific antigen binding proteins that comprise an antigen-binding regions specific for a tumor-associated antigen (TAA), an antigen-binding region that specifically binds an epitope of a γδ T cell receptor (TCR), a γδ T cell-activating cytokine, and optionally, a γδ T cell co-stimulatory agonist. The γδ T cell-activating cytokine preferably is at least 5 one of an interleukin 21 receptor (IL21R) agonist and an interleukin 15 receptor (IL15R) agonist. The γδ T cell co-stimulatory agonist cytokine preferably is at least one of a 4-1BB agonist, a CD27 agonist and a GITR agonist. The multispecific antigen binding proteins of the invention specifically redirect and activate γδ T cell to lyse targeted tumor cells. The invention further relates to the use of such multispecific antigen binding proteins in the treatment of cancer, preferably a cancer 10 expressing the TAA.

The invention relates to a CD19 and CD70 targeted double-target chimeric antigen receptor and application thereof, the CD19 and CD70 targeted double-target chimeric antigen receptor comprises an extracellular antigen binding domain, a hinge region, a transmembrane domain, an intracellular costimulatory domain and an intracellular signal transduction domain, and the extracellular antigen binding domain has specific binding ability to CD19 and CD70. The double-target chimeric antigen receptor structure has a treatment effect of targeting double antigens or single antigens, can be used for preparing immune effector cells targeting CD19 and CD70, and provides a treatment or improvement approach for diseases related to CD19 and CD70 double expression or CD19 / CD70 single expression.

The invention provides a chimeric antigen receptor for regulating and controlling a signal time sequence and application of the chimeric antigen receptor. The chimeric antigen receptor sequentially comprises a signal peptide, an extracellular domain, a transmembrane domain and an intracellular domain from an N terminal to a C terminal, the extracellular structural domain comprises an antigen recognition region and a hinge region; the intracellular domain comprises a costimulatory signal transduction region and a CD3 [zeta] intracellular region variant; the CD3 [zeta] intracellular region variant comprises three ITAMs, and the arrangement sequence of the ITAMs is ITAM3-ITAM2-ITAM1 from the N end to the C end. Compared with a conventional chimeric antigen receptor containing a wild CD3 zeta intracellular region, the chimeric antigen receptor provided by the invention can significantly enhance the functional activity of immune cells expressing the chimeric antigen receptor, which is specifically embodied in stronger multiplication capacity and durability, and significantly improves the antigen sensitivity and targeted killing efficacy.

The present invention provides for chimeric antigen receptor constructs capable of being expressed in dendritic cells (DCs), and DCs modified to express one or more chimeric antigen receptors (CARs) as well as compositions comprising these modified DCs and methods of stimulating an adaptive immune response in a subject. The intracellular domain of the CAR comprises a toll-interleukin receptor (TIL) intracellular signalling domain and a costimulating domain selected from CD3 signalling domain, CD28 signalling domain and a combined CD28 and CD3 signalling domain.

Provided herein are novel αPD-L1 antibodies and methods of using such antibodies for the treatment of cancers. In some embodiments, the antibodies are αPD-L1×αCD28 bispecific antibodies. Such antibodies enhance anti-tumor activity by providing a costimulatory signal for T-cell activation against tumor cells while advantageously also blocking inhibitory PD-L1:PD-1 pathway interactions.

The application provides an immune cell preparation method capable of reversing tumor microenvironment immunosuppression signals and application thereof. The method for reversing the inhibitory signals is to replace the intracellular segment of a TIGIT receptor with a 4-1BB costimulatory domain and an IL-18R and a CD3 intracellular segment, and the immune cells expressing the chimeric antigen receptor recognize CD155 in a tumor microenvironment through TIGIT, avoid loss of function or exhaustion of the immune cells, and stimulate the immune cells to exert stronger tumor killing activity.

The invention provides a nucleic acid construct which comprises an immune response regulatory sequence and a coding sequence of a reporter gene driven by a promoter sequence, and the immune response regulatory sequence comprises a transcription factor binding regulatory element RE which is co-stimulated and regulated by transcription factors AP-1 and CD28. The invention also provides an in-vitro immune effector function reporter gene cell model containing the nucleic acid construct, and the cell model can realize effector function activity determination performance of sensitive and potent signals so as to evaluate ADCC and ADCP killing action mechanisms and titers mediated by antibody-dependent disease cells designed by an Fc structural domain of a therapeutic antibody product. In addition, the immunosuppression and regulation efficacy of a targeted CTLA-4 or Abatacept mediated treatment method on a CD28 co-activation pathway can be evaluated.

This application provides a BCMA-targeting chimeric antigen receptor (CAR) comprising a BCMA-binding domain and an intracellular costimulatory domain derived from DAP10. Also provided are engineered immune effector cells (e.g., NK cells) containing the chimeric antigen receptor. Pharmaceutical compositions, kits, and methods for treating cancer are also provided.

The application discloses a chimeric antigen receptor targeting CEA and a T cell containing the chimeric antigen receptor targeting CEA. The chimeric antigen receptor is composed of a nanobody recognizing a CEA antigen, an extracellular hinge region, a transmembrane region, an intracellular signal region, a self-cleavage polypeptide T2A and a hyaluronidase in sequence. The chimeric antigen receptor can efficiently recognize the CEA antigen, and CD28 and CD137 are used as a costimulatory signal region to activate T cells, thereby playing a cellular immune role, and specifically killing CEA-positive tumor cells, and thus having an important application prospect in the field of tumor cell immunotherapy.

The invention discloses a bispecific antibody targeting T cells and Her2 positive cells and a fusion protein connected in series with 4-1BBL. Belongs to the technical field of biology. The fusion protein is of a heterotetramer structure formed by connecting two similar heavy polypeptide chains and two similar light polypeptide chains through disulfide bonds, wherein the similar heavy polypeptide chains comprise a heavy chain variable region of a Her2 targeting antibody, a human IgG1 Fc region and a human 4-1BBL extracellular region; the light polypeptide-like chain comprises a light chain variable region of a Her2 targeting antibody, a human antibody light chain constant region and a single chain variable region fragment of a CD3 targeting antibody. The fusion protein can specifically bind to Her2 positive tumor cells and CD3 molecules on the surfaces of T cells at the same time, and provides a key co-stimulation signal by using 4-1BBL connected in series, so that the killing function of the T cells is efficiently activated and enhanced in the local part of the tumor. The fusion protein provides a novel candidate strategy with stronger curative effect, more lasting effect and better safety for immunotherapy of Her2 positive tumors.

The invention discloses a chimeric antigen receptor targeting EGFRvIII and application of the chimeric antigen receptor. The chimeric antigen receptor sequentially comprises an EGFRvIII targeting nucleic acid aptamer, a transmembrane domain and an intracellular signal domain from an N end to a C end, the EGFRvIII targeted nucleic acid aptamer is an EGFRvIII specific DNA aptamer obtained on the basis of SELEX (systematic evolution of ligands by exponential enrichment) screening, can only be combined with an extracellular domain of the EGFRvIII, and is not combined with an EGFR (epidermal growth factor receptor) wild type; the intracellular signal domain comprises a costimulatory signal domain and an activation signal domain, the C end of the costimulatory signal domain is connected with the N end of the activation signal domain, and the EGFRvIII specific nucleic acid aptamer screened based on SELEX is adopted as a targeting domain, can only be specifically combined with the extracellular domain of EGFRvIII positive tumor cells, and is not subjected to cross combination with EGFR wild cells and normal cells, so that the EGFRvIII specific nucleic acid aptamer can be used for detecting EGFRvIII positive tumor cells, and the EGFRvIII specific nucleic acid aptamer can be used for detecting EGFRvIII positive tumor cells. The problem of off-target killing caused by the fact that a common antibody scFv fragment of a traditional chimeric antigen receptor (CAR) is easily combined with a wild type EGFR is fundamentally avoided.

The present invention is directed to a humanized BCMA single-chain variable fragment (scFv), comprising VH having the amino acid sequence of SEQ ID NO: 4 and VL having the amino acid sequence of SEQ ID NO: 5. The present invention is also directed to a BCMA chimeric antigen receptor fusion protein comprising from N-terminus to C-terminus: (i) a single-chain variable fragment (scFv) of the present invention, (ii) a transmembrane domain, (iii) at least one co-stimulatory domains, and (iv) an activating domain. A preferred co-stimulatory domain is CD28 or 41-BB. The humanized BCMA-CAR-T cells have specific killing activity with secretion of cytokine IFN-gamma in CAR-T cells in vitro and in vivo.

Provided herein is a composition comprising, a cell, comprising nucleic acids encoding a chimeric antigen receptor (CAR) and one or more of signaling proteins selected from K13-vFLIP, MC159-vFLIP, cFLIP-L, cFLIP-p22, HTLV1-Tax and HTLV2-Tax, wherein the CAR comprises an a) extracellular antigen specific domain, b) a transmembrane domain and c) an intracellular signaling domain comprising an immunoreceptor tyrosine-based activation motif (ITAM); wherein c) is located at the C-terminus of the chimeric receptor. In some embodiments, the CAR further comprises one or more co-stimulatory domains. Also provided herein are methods for treating diseases using the compositions described herein. Further provided herein is a kinase inhibitor for use in therapeutic methods described herein.

The present invention provides thymic T regulatory cells (ThyTreg cells) that encode or alternatively express a chimeric antigen receptor (CAR) comprising an extracellular domain, a hinge region, a transmembrane domain, and an intracellular domain, wherein the intracellular domain comprises a cytoplasmic costimulatory domain having a sequence having at least 85% identity with SEQ ID NO: 1, and a cytoplasmic stimulatory domain. The present invention also provides compositions and uses in immunotherapy.

The present invention relates to a chimeric antigen receptor (CAR) (anti-B7H3 CAR) that binds to B7 homolog 3 protein (B7H3), the anti-B7H3 CAR comprising: (a) an extracellular antigen binding moiety that is specific for human B7H3; (b) a co-stimulatory signaling domain; and (c) a cytoplasmic signaling domain. Also provided herein are immune cells expressing the anti-B7H3 CAR, optionally in combination with an armor polypeptide, and the use of the immune cells in cancer therapy.

The present invention relates to the field of adoptive immune cell therapy, in particular adoptive T cell therapy. The present invention provides a conversion receptor which is capable of effectively converting an immunosuppressive signal of TGF [beta], which is normally present in the hostile tumor environment of a solid tumor, into a co-stimulatory signal, thereby improving T cell activation, and which can be safely used in therapy. Also provided are nucleic acids encoding the transforming receptors, cells expressing the receptors and pharmaceutical compositions comprising the cells, in particular for the treatment of cancer or infectious diseases, such as adoptive T cell therapy by solid tumors.

The invention is directed to a bispecific chimeric antigen receptor, comprising: (a) at least two antigen-specific targeting regions; (b) an extracellular spacer domain; (c) a transmembrane domain; (d) at least one co-stimulatory domain; and (e) an intracellular signaling domain, wherein each antigen-specific targeting region comprises an antigen-specific single chain Fv (scFv) fragment, and binds a different antigen, and wherein the bispecific chimeric antigen receptor is co-expressed with a therapeutic control. The invention also provides methods and uses of the bispecific chimeric antigen receptors.

The present application relates to signal conversion receptors, and specifically provides a signal conversion receptor comprising an extracellular region, a transmembrane region and an intracellular region, wherein the intracellular region comprises a CD25 intracellular domain, and optionally further comprises an intracellular domain of a costimulatory signaling molecule. An immune effector cell expressing the signal conversion receptor has a higher positive rate, activation level and target cell killing ability compared with a control cell.

Disclosed are immune cell enhancers containing a first moiety that binds a cytokine receptor on the immune cell, and a second moiety that binds a co-stimulatory receptor on the immune cell. Also disclosed are adoptive cell therapeutic systems. The system includes a) a chimeric antigen receptor (CAR) immune cell comprising a CAR that comprises an extracellular domain that binds an antigen present on a cancer cell, a transmembrane domain, and an endodomain comprising a co-stimulatory region, but not a stimulatory region comprising a CD3 protein and b) a CAR-enhancer comprising a first moiety that binds an extracellular domain on the CAR immune cell and a second moiety that binds a cytokine receptor on the immune cell and uses thereof to treat cancer. Further disclosed are pharmaceutical compositions containing an effective amount of the ICE or the system and a pharmaceutically acceptable carrier. And methods of treating cancer therewith.

The present invention relates to a chimeric antigen receptor comprising a ligand binding domain, a transmembrane domain, a costimulatory domain and an intracellular signaling domain wherein the costimulatory domain comprises a mutated CD27 intracellular region. The invention also relates to engineered immune cells comprising such chimeric antigen receptors and their use in the treatment of diseases, such as cancer, autoimmune diseases, infections.

The invention relates to a triple-effect T cell adapter for targeting T cell lymphoma TRBC1. The invention discloses a TRBC1-targeted triple-effect T cell adapter which is composed of an Fc region, a hinge region, a first Fab arm and a second Fab arm, and a third targeting module is covalently connected to the C end of the Fc region to form a Y-shaped triple-head antibody. The first Fab arm and the second Fab arm are respectively combined with TRBC1 and CD3, and the third Fab arm is combined with CD28 or CD137, so that three functions of tumor recognition, T cell recruitment and co-stimulation amplification are integrated. The two polypeptide chains are heterodimerized through CH3 region button mutation, and correct assembly is ensured. The structure supports module interchange, programmable regulation and control of synergistic signals, significantly enhances TRBC1 positive T cell lymphoma killing, reduces toxicity to normal T cells, has high activity and a wide safety window, and is suitable for preparation of related drugs.

The application discloses an antigen-engineered nanovesicle vaccine (AN-FV) and a preparation method and application thereof. The vaccine is formed by fusion of vesicles of tumor cell membranes obtained by pretreatment of functionalized nanometer preparations and vesicles of mature dendritic cell membranes; the functionalized nanometer preparations contain autophagy inhibiting siRNA and an immunogenicity enhancer, and can synergistically improve MHC-I expression of tumor cells and antigen immunogenicity. The vaccine of the application simultaneously presents high-density MHC-I-antigen peptide complexes and CD80 / CD86 costimulatory molecules on the surface of a single particle, simulates an immune synapse in a nanometer scale, and thus efficiently activates tumor-specific T cells. The vaccine integrates antigen source engineering, physiologicalization of costimulatory signals and nanometer platform integration, and provides a new scheme for overcoming the treatment bottleneck of immune "cold" tumors such as pancreatic cancer.

The invention provides an NK cell, a chimeric antigen receptor and a pharmaceutical composition and application of the chimeric antigen receptor, the NK cell expresses the chimeric antigen receptor, and the chimeric antigen receptor fusion protein comprises a targeted TROP2 single-chain antibody, a transmembrane structural domain, a co-stimulation structural domain, an activation structural domain, IL-15 protein and a CXCR2 chemotactic factor from the N terminal to the C terminal. In the invention, overexpression of CXCR2 can improve the killing efficiency of CAR NK, and the killing efficiency can be improved only by combining the membrane-combined IL15 with CXCR2 in the two forms of IL15.

The invention discloses a method for in-vitro broad-spectrum stimulation of immune checkpoint up-regulation and application, the method comprises the following steps: placing a Jurkat cell line in an RPMI-1640 culture medium containing 10% of fetal calf serum and 1% of penicillin-streptomycin, carrying out in-vitro stimulation for 24-72 hours by adopting PHA with a concentration of 0.1-5 [mu] g / mL under the conditions of 37 DEG C and 5% of CO2, activating NF-kB and / or MAPK signal channels, and carrying out in-vitro broad-spectrum stimulation of immune checkpoint up-regulation. The broad-spectrum up-regulation of co-stimulatory immune checkpoints of CD28, CD40L, ICOS and the like and co-inhibitory immune checkpoints of PD-1, LAG-3, CTLA-4 and the like is realized, and the high expression state can be maintained for at least 72 hours after the PHA is removed. The invention also discloses the in-vitro broad-spectrum immune checkpoint positive T cell model constructed by the method, and the up-regulation of immune checkpoints in the model is accompanied by the increase of dose-dependent secretion of various cytokines. The model can replace a traditional model, is applied to toxicology and pharmacology research of immune checkpoint antagonists and combined synergistic effect and immune checkpoint regulation and control mechanism research, is simple and convenient to operate and high in repeatability, and provides an efficient tool for research and development of related drugs.

The present disclosure provides a CAR-T composition directed to a CAR comprising (i) an extracellular domain comprising an antigen-binding domain, (ii) a transmembrane domain, and (iii) an intracellular domain comprising a costimulatory endodomain, wherein the costimulatory endodomain comprises an intracellular signaling domain derived from 4-1BB / CD137 and five additional amino acids. The present disclosure also provides vectors, compositions, and therapeutic methods using the antigen-binding molecule and engineered immune cells comprising the CAR. The CAR compositions provided herein can be used to treat certain cancers.

The present invention provides a method for producing CAR-T cells, the method comprising: a first step for stimulating a cell population containing unstimulated CAR-T cells under condition [A]; and a second step for stimulating a cell population containing CAR-T cells after the first step under condition [B]. [A] [Number of T cells (cells) in a cell population containing unstimulated CAR-T cells]:[Number of antigen recognition factors (pmol)]:[Number of costimulatory factors (pmol)] = 106:0.1-0.83:0.2-1.7; [B] [Number of T cells (cells) in a cell population containing CAR-T cells after first step]:[Number of antigen recognition factors (pmol)]:[Number of costimulatory factors (pmol)] = 106:0.05-0.17:0.05-0.28 (provided that the sum of the number of antigen recognition factors and the number of costimulatory factors in [B] is smaller than that in [A]).

The present invention relates to a chimeric costimulatory antigen receptor (CoStAR) useful in adoptive cell therapy (ACT), and cells comprising the CoStAR. The CoStAR can act as a modulator of cellular activity enhancing responses to defined antigens. The present invention also provides CoStAR proteins, nucleic acids encoding the CoStAR and therapeutic uses thereof.